Mechanism of inhibition defines CETP activity: a mathematical model for CETP in vitro

Laura K. Potter¹^,2^,*, Dennis L. Sprecher, Max C. Walker and Frank L. Tobin

^* Scientific Computing and Mathematical Modeling, GlaxoSmithKline, King of Prussia, PA
GlaxoSmithKline, Research Triangle Park, NC and Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, PA
Scientific Computing and Mathematical Modeling, GlaxoSmithKline, King of Prussia, PA

² To whom correspondence should be addressed. e-mail: laura.potter{at}syngenta.com

Because cholesteryl ester transfer protein (CETP) inhibitionis a potential HDL-raising therapy, interest has been raisedin the mechanisms and consequences of CETP activity. To explorethese mechanisms and the dynamics of CETP in vitro, a mechanisticmathematical model was developed based upon the shuttle mechanismfor lipid transfer. Model parameters were estimated from eightpublished experimental datasets, and the resulting model capturesobserved dynamics of CETP in vitro. Simulations suggest theshuttle mechanism yields behaviors consistent with experimentalobservations. Three key findings predicted from model simulationsare: 1) net CE transfer activity from HDL to VLDL and LDL canbe significantly altered by changing the balance of homoexchangeversus heteroexchange of neutral lipids via CETP; 2) lipemia-inducedincreases in CETP activity are more likely caused by increasesin lipoprotein particle size than particle number; and 3) theinhibition mechanisms of the CETP inhibitors torcetrapib andJTT-705 are significantly more potent than a classic competitiveinhibition mechanism with the irreversible binding mechanismhaving the most robust response. In summary, the model providesa plausible representation of CETP activity in vitro, corroboratesstrong evidence for the shuttle hypothesis, and provides newinsights into the consequences of CETP activity and inhibitionon lipoproteins.

Supplementary key words cholesteryl ester transfer protein • reverse cholesterol transport • lipoprotein metabolism • lipemia • CETP inhibitors

Abbreviations: apoB, apolipoprotein B; CETP, cholesteryl ester transfer protein; CE, cholesterol ester; CHD, coronary heart disease; LTIP, lipid transfer inhibitor protein; TG, triglyceride

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